Circulating HIV-Specific Interleukin-21+CD4+ T Cells Represent Peripheral Tfh Cells with Antigen-Dependent Helper Functions

Abstract

A central effort in HIV vaccine development is to generate protective broadly neutralizing antibodies, a process dependent on T follicular helper (Tfh) cells. The feasibility of using peripheral blood counterparts of lymph node Tfh cells to assess the immune response and the influence of viral and vaccine antigens on their helper functions remain obscure. We assessed circulating HIV-specific IL-21(+)CD4(+) T cells and showed transcriptional and phenotypic similarities to lymphoid Tfh cells, and hence representing peripheral Tfh (pTfh) cells. pTfh cells were functionally active and B cell helper quality differed depending on antigen specificity. Furthermore, we found higher frequency of pTfh cells in peripheral blood mononuclear cell specimens from the ALVAC+AIDSVAX (RV144) HIV vaccine trial associated with protective antibody responses compared to the non-protective DNA+Ad5 vaccine trial. Together, we identify IL-21(+)CD4(+) T cells as pTfh cells, implicating them as key populations in the generation of vaccine-evoked antibody responses.

Preservation of Peripheral T Follicular Helper Cell Function in HIV Controllers

“…5B). Taken together, our data demonstrate that certain memory B cell subsets are correlated with Env-specific IL-21 ϩ CXCR5 ϩ CD4 ϩ T cells but not bulk CXCR5 ϩ CD4 ϩ T cells, supporting our previous study showing that IL-21 secretion may better identify pTfh cells (19). Moreover, our partially divergent association in HIV progressors versus controllers suggests a functional impairment of HIV-specific pTfh cells in HIV progressors, in accordance with data for GC Tfh cells (12).…”

“…Thus, we next interrogated T cell markers involved in mediating B cell help to further address the role of viral load in helper T cell interactions with B cells. While we and others have established that circulating CXCR5 ϩ CD4 ϩ T cells are heterogeneous (19), there is a large body of evidence showing that IL-21-secreting HIV-specific CD4 T cells comprise a small subset within this T cell subpopulation and provide B cell help (19). Interestingly, however, we found a strong inverse association between the frequency of CXCR5 ϩ CD4 ϩ T cells and gp120-specific B cells (rho ϭ Ϫ0.44; P ϭ 0.01) in all groups of HIV-infected individuals (Fig.…”

“…As expression of the CXCR5 chemokine receptor on CD4 ϩ T cells ostensibly defines a subset of pTfh cells in peripheral blood (7,19,21), we assessed whether specific gp120-specific B cell memory subsets were associated with CXCR5 ϩ CD4 ϩ T cells. Overall, gp120-specific RM and IM cells were significantly expanded in HIV EC (P ϭ 0.0004 and P ϭ 0.04, respectively), while the AM cell subset was larger in HIV progressors (P ϭ 0.01), as was the TLM subset, albeit to a lower degree ( Fig.…”

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…Interestingly, IgG responses to V1‐V2 were higher and were associated with a decreased risk of infection acquisition only in individuals with the HLA‐DPB1*13 class II allele, while Env‐specific IgA responses were associated with an enhanced infection risk only in individuals with HLA‐DQB1*06, two class II alleles that were both common (present at frequencies of >10%) in the RV144 vaccine trial participants 208. Env‐specific CD4 + T cells directed against V2 were the most common T‐cell response induced by the RV144 vaccine regimen209; furthermore, RV144 vaccinees exhibited higher frequencies of circulating HIV‐specific IL‐21‐producing CD4 + T cells than participants in other trials of non‐protective HIV vaccines 210. Together, these observations suggest an important role for qualitative features of the vaccine‐induced CD4 + T‐cell response in determining the protective capacity of the antibody response elicited—a relationship that may prove even more critical for bnAb induction.…”

Somatic mutation-associated T follicular helper cell elevation in lung adenocarcinoma

“…7 Infection models have revealed that circulating Tfh function differently from those in lymphoid tissue and correlate with opposing outcomes. 8 In human breast cancers and mouse models of colorectal cancer, increased Tfh correlates with increased survival. 9,10 …”